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Adipose-Derived Mesenchymal Stem Cell Treatments and Available Formulations

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Adipose-Derived Mesenchymal Stem Cell Treatments and Available Formulations Current Reviews in Musculoskeletal Medicine (2020) 13:264–280 https://doi.org/10.1007/s12178-020-09624-0 STEM CELLS IN ORTHOPAEDIC SURGERY (J DRAGOO AND K JONES, SECTION EDITORS) Adipose-Derived Mesenchymal Stem Cell Treatments and Available Formulations Kyle N. Kunze1 & Robert A. Burnett1 & Joshua Wright-Chisem2 & Rachel M. Frank3 & Jorge Chahla1 Published online: 23 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020 Abstract Purpose of Review The use of human adipose-derived mesenchymal stem cells (ADSCs) has gained attention due to its potential to expedite healing and the ease of harvesting; however, clinical evidence is limited, and questions concerning optimal method of delivery and long-term outcomes remain unanswered. Recent Findings Administration of ADSCs in animal models has been reported to aid in improved healing benefits with enhanced repair biomechanics, superior gross histological appearance of injury sites, and higher concentrations of growth factors associated with healing compared to controls. Recently, an increasing body of research has sought to examine the effects of ADSCs in humans. Summary Several available processing techniques and formulations for ADSCs exist with evidence to suggest benefits with the use of ADSCs, but the superiority of any one method is not clear. Evidence from the most recent clinical studies available demonstrates promising outcomes following treatment of select musculoskeletal pathologies with ADSCs despite reporting variability among ADSCs harvesting and processing; these include (1) healing benefits and pain improvement for rotator cuff and Achilles tendinopathies, (2) improvements in pain and function in those with knee and hip osteoarthritis, and (3) improved cartilage regeneration for osteochondral focal defects of the knee and talus. The limitation to most of this literature is the use of other therapeutic biologics in combination with ADSCs. Additionally, many studies lack control groups, making establishment of causation inappropriate. It is imperative to perform higher-quality studies using consistent, predictable control populations and to standardize formulations of ADSCs in these trials. Keywords Adipose . Stem cells . ADSCs . Biologics . Formulations . Regenerative medicine Introduction that have the ability to differentiate into several lineages, is one such adjunct with increasing interest as they can be utilized for The use of biologic adjuncts as both operative and non- clinical benefit by expediting physiological processes responsi- operative treatments for orthopedic pathologies has become of ble for healing. Several sources from adult progenitor cells have recent interest due to potential healing benefits. [1–5] been reported in the literature including bone marrow mesen- Administration of progenitor cells, defined as pluripotent cells chymal stem cells and peripheral blood stem cells; [6, 7]more recently, adipose-derived mesenchymal stem cells (ADSCs) This article is part of the Topical Collection on Stem Cells in Orthopaedic have been recognized as an alternative source of stromal cells Surgery thought to have equivalent differentiation capacity. A primary reason for increased interest in the use of ADSCs * Jorge Chahla for clinical applications manifests from the ease with which they [email protected] are harvested relative to other stromal cells, as subcutaneous stores in the infrapatellar fat pad and buttocks/flank allow for a 1 Department of Orthopaedic Surgery, Division of Sports Medicine, less invasive isolation process with a similar multi-lineage poten- Rush University Medical Center, Chicago, IL, USA tial. [8] Indeed, these minimally invasive harvesting techniques 2 Department of Orthopaedic Surgery, Hospital for Special Surgery, are associated with lower donor site morbidity and pain and New York, NY, USA fewer complications than the harvesting of other stromal cells, 3 Department of Orthopaedic Surgery, Division of Sports Medicine, and lipoaspirate has been demonstrated to result in higher University of Colorado School of Medicine, Boulder, CO, USA Curr Rev Musculoskelet Med (2020) 13:264–280 265 progenitor cell yields than bone marrow aspirates [9]. Other pro- osteogenic-specific molecular pathways which utilize migra- posed benefits of ADSCs include greater availability, with re- tion, molecular adhesion, and differential signaling to increase ports of up to 10% nucleated cells from ADSCs versus 0.001– bone production. [22] Most theories accept the premise that 0.01% of bone marrow-derived mesenchymal stem cells, a low these cascades begin with a commitment step from the stem rate of complications, and high proliferative potential and rapid cell precursor into the osteogenic lineage through molecular expansion. [10–13] signals including transforming growth factor (TGF)-β,bone Despite increasing use, several limitations to ADSCs still morphogenic protein (BMP) family, fibroblast growth factor exist. While controlled laboratory studies involving the use of (FGF), and Wnt/β-Catenin proteins. [22] The cellular and ADSCs as an augment for the treatment of common orthope- molecular mechanisms that underlie osteogenic differentiation dic pathologies such as focal osteochondral defects and rotator via ADSCs are complex and out of scope of the current re- cuff tendinopathy have reported promising results in animal view; however, few major mechanisms and prevalent theories models, [14–17] few studies involving human subjects exist. of osteogenic differentiation are presented below. [18–21] Furthermore, most of these studies have inconsistent BMP has been implicated as one of the primary initiators of protocols and formulations of ADSCs, making it difficult to the signaling cascade for ADSC-mediated osteogenesis. compare results between studies. Additionally, it is still un- Studies have shown that BMP initiates the cascade via ligand clear if ADSCs act directly by repairing the tissue or through binding of serine/threonine kinase cell surface receptors. [23] signaling environmental molecules to aid the repair of the The next step involves these activated receptor kinases phos- tissue. [22] The current article presents a comprehensive re- phorylating transcription factor SMADs, which subsequently view of the mechanisms of action of ADSCs from the basic form a heterodimeric complex and promote gene expression science literature and available formulations of ADSCS. and osteogenic differentiation. [24] BMP-2 induces the phos- Additionally, this review discusses evidence for the safety phorylation of Smad 1/5/8 and the transactivation of a BMP/ and efficacy of ADSCs for orthopedic pathologies and injuries Smad-responsive construct (12xSBE-Oc-pGL3). [25] in both animal models as well as clinical trials with an empha- Furthermore, Ducy et al. [26] showed that BMPs were able to sis on clinical and functional outcomes as well as variability in increase the transcription of core-binding factor-1/Runt-related harvesting and processing protocols. Finally, future directions family 2(Cbfa1/Runx2), a molecule that is well known to be for the use of ADSCs in the context of the current evidence in essential for the commitment process of osteoblastic lineage. this review will be presented. The Notch pathway has also been found to be heavily implicat- ed in the role of osteogenic differentiation through interactions with BMP-2, which results in increased expression of Delta1/ Proposed Mechanisms of Action Jagged1-activated Notch. [25, 27] Interestingly, overexpression from the Basic Science Literature of the Notch intracellular domain (NICD) impairs osteogenesis. Notch has been demonstrated to oppose the effects of BMP-2 The multipotent nature of ADSCs allows for the potential to and Wnt-3a on alkaline phosphatase activity, which is normally differentiate into several different lineages including osteo- upregulated by these markers. Furthermore, Notch overexpres- genic, chondrogenic, adipogenic, and myogenic cell lines. sion decreases the transactivating effect of Wnt-3a, cytoplasmic Given the proposed beneficial effects of the use of ADSC in β-catenin levels, and Wnt-dependent gene expression. NICD bone, tendon and muscle healing, a better understanding of the overexpression prevents BMP-2 and Wnt biological effects by downstream effects induced by ADSC at the molecular level suppressing Wnt, but not BMP signaling. [25] This is a clini- is imperative to clarify how these outcomes are mediated. cally relevant consideration in appropriately culturing and ma- Furthermore, such clarification will help better understand nipulating cellular conditions to optimize osteogenic differenti- ADSCs as a biologic adjunct in general, the spectrum of their ation from ADSCs. use in repair of common musculoskeletal injuries, and poten- Grottkau et al. [28] harvested ADSCs from normal rats and tially aid in the optimization of ADSCs formulations. attempted to utilize BMP-2 enhanced ADSCs to restore criti- cal size cranial defects. There were three populations studied: Proposed Mechanisms of Osteogenesis one group with deficits filled with alginate gel alone, another with alginate gel and normal ADSCs, and finally alginate gel While the specific mechanisms of osteogenesis from ADSCs with BMP-2 transfected ADSCs. The study concluded that are complex and not completely understood, there are several alginate gel with BMP-2-enhanced ADSCs was necessary proposed mechanisms by which osteogenic differentiation is for critical size defect repair. thought
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